Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.

TitleDissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2018
AuthorsBroce IJ, Tan CHong, Fan CChieh, Jansen I, Savage JE, Witoelar A, Wen N, Hess CP, Dillon WP, Glastonbury CM, Glymour M, Yokoyama JS, Elahi FM, Rabinovici GD, Miller BL, Mormino EC, Sperling RA, Bennett DA, McEvoy LK, Brewer JB, Feldman HH, Hyman BT, Pericak-Vance M, Haines JL, Farrer LA, Mayeux R, Schellenberg GD, Yaffe K, Sugrue LP, Dale AM, Posthuma D, Andreassen OA, Karch CM, Desikan RS
JournalActa Neuropathol
Date Published2018 Nov 09
ISSN1432-0533
Abstract

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10), MINK1 (chromosome 17, meta-p = 1.98 × 10) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10 and closest gene = MYBPC3, meta-p = 5.62 × 10). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

DOI10.1007/s00401-018-1928-6
Alternate JournalActa Neuropathol.
PubMed ID30413934
Grant List225989 / / Norges Forskningsråd /
K01 AG049152 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
237250/EU JPND / / Norges Forskningsråd /
K01AG049152 / / National Institutes of Health /
K01 AG046374 / AG / NIA NIH HHS / United States
213837 / / Norges Forskningsråd /
223273 / / Norges Forskningsråd /
AG046374 / / National Institutes of Health /